Mitochondria are essential organelles that regulate cellular energy homeostasis and cell death. The removal of damaged mitochondria through autophagy, a process called mitophagy, is thus critical for ...maintaining proper cellular functions. Indeed, mitophagy has been recently proposed to play critical roles in terminal differentiation of red blood cells, paternal mitochondrial degradation, neurodegenerative diseases, and ischemia or drug-induced tissue injury. Removal of damaged mitochondria through autophagy requires two steps: induction of general autophagy and priming of damaged mitochondria for selective autophagic recognition. Recent progress in mitophagy studies reveals that mitochondrial priming is mediated either by the Pink1-Parkin signaling pathway or the mitophagic receptors Nix and Bnip3. In this review, we summarize our current knowledge on the mechanisms of mitophagy. We also discuss the pathophysiological roles of mitophagy and current assays used to monitor mitophagy.
Necroptosis plays an essential role in acute kidney injury and is mediated by receptor-interacting protein kinase 1 (RIPK1), receptor-interacting protein kinase 3 (RIPK3), and mixed lineage kinase ...domain-like pseudokinase (MLKL). A novel RIPK3 inhibitor, compound 42 (Cpd-42) alleviates the systemic inflammatory response. The current study was designed to investigate whether Cpd-42 exhibits protective effects on acute kidney injury and reveal the underlying mechanisms.
The effects of Cpd-42 were determined in vivo through cisplatin- and ischaemia/reperfusion (I/R)-induced acute kidney injury and in vitro through cisplatin- and hypoxia/re-oxygenation (H/R)-induced cell damage. Transmission electron microscopy and periodic acid-Schiff staining were used to identify renal pathology. Cellular thermal shift assay and RIPK3-knockout mouse renal tubule epithelial cells were used to explore the relationship between Cpd-42 and RIPK3. Molecular docking and site-directed mutagenesis were used to determine the binding site of RIPK3 with Cpd-42.
Cpd-42 reduced human proximal tubule epithelial cell line (HK-2) cell damage, necroptosis and inflammatory responses in vitro. Furthermore, in vivo, cisplatin- and I/R-induced acute kidney injury was alleviated by Cpd-42 treatment. Cpd-42 inhibited necroptosis by interacting with two key hydrogen bonds of RIPK3 at Thr94 and Ser146, which further blocked the phosphorylation of RIPK3 and mitigated acute kidney injury.
Acting as a novel RIPK3 inhibitor, Cpd-42 reduced kidney damage, inflammatory response and necroptosis in acute kidney injury by binding to sites Thr94 and Ser146 on RIPK3. Cpd-42 could be a promising treatment for acute kidney injury.
Acute kidney injury (AKI) is a syndrome of abrupt loss of renal functions. The underlying pathological mechanisms of AKI remain largely unknown. BCL2-interacting protein 3 (BNIP3) has dual functions ...of regulating cell death and mitophagy, but its pathophysiological role in AKI remains unclear. Here, we demonstrated an increase of BNIP3 expression in cultured renal proximal tubular epithelial cells following oxygen-glucose deprivation-reperfusion (OGD-R) and in renal tubules after renal ischemia-reperfusion (IR)-induced injury in mice. Functionally, silencing Bnip3 by specific short hairpin RNAs in cultured renal tubular cells reduced OGD-R-induced mitophagy, and potentiated OGD-R-induced cell death. In vivo, Bnip3 knockout worsened renal IR injury, as manifested by more severe renal dysfunction and tissue injury. We further showed that Bnip3 knockout reduced mitophagy, which resulted in the accumulation of damaged mitochondria, increased production of reactive oxygen species, and enhanced cell death and inflammatory response in kidneys following renal IR. Taken together, these findings suggest that BNIP3-mediated mitophagy has a critical role in mitochondrial quality control and tubular cell survival during AKI.
Mitochondria are essential for the activity, function and viability of eukaryotic cells and mitochondrial dysfunction is involved in the pathogenesis of acute kidney injury (AKI) and chronic kidney ...disease, as well as in abnormal kidney repair after AKI. Multiple quality control mechanisms, including antioxidant defence, protein quality control, mitochondrial DNA repair, mitochondrial dynamics, mitophagy and mitochondrial biogenesis, have evolved to preserve mitochondrial homeostasis under physiological and pathological conditions. Loss of these mechanisms may induce mitochondrial damage and dysfunction, leading to cell death, tissue injury and, potentially, organ failure. Accumulating evidence suggests a role of disturbances in mitochondrial quality control in the pathogenesis of AKI, incomplete or maladaptive kidney repair and chronic kidney disease. Moreover, specific interventions that target mitochondrial quality control mechanisms to preserve and restore mitochondrial function have emerged as promising therapeutic strategies to prevent and treat kidney injury and accelerate kidney repair. However, clinical translation of these findings is challenging owing to potential adverse effects, unclear mechanisms of action and a lack of knowledge of the specific roles and regulation of mitochondrial quality control mechanisms in kidney resident and circulating cell types during injury and repair of the kidney.
Plasma SARS-CoV-2 RNA may represent a viable diagnostic alternative to respiratory RNA levels, which rapidly decline after infection. Quantitative PCR with reverse transcription (RT-qPCR) reference ...assays exhibit poor performance with plasma, probably reflecting the dilution and degradation of viral RNA released into the circulation, but these issues could be addressed by analysing viral RNA packaged into extracellular vesicles. Here we describe an assay approach in which extracellular vesicles directly captured from plasma are fused with reagent-loaded liposomes to sensitively amplify and detect a SARS-CoV-2 gene target. This approach accurately identified patients with COVID-19, including challenging cases missed by RT-qPCR. SARS-CoV-2-positive extracellular vesicles were detected at day 1 post-infection, and plateaued from day 6 to the day 28 endpoint in a non-human primate model, while signal durations for 20-60 days were observed in young children. This nanotechnology approach uses a non-infectious sample and extends virus detection windows, offering a tool to support COVID-19 diagnosis in patients without SARS-CoV-2 RNA detectable in the respiratory tract.
High-mobility group box 1 (HMGB1) is a highly abundant DNA-binding protein that can relocate to the cytosol or undergo extracellular release during cellular stress or death. HMGB1 has a functional ...versatility depending on its cellular location. While intracellular HMGB1 is important for DNA structure maintenance, gene expression, and autophagy induction, extracellular HMGB1 acts as a damage-associated molecular pattern (DAMP) molecule to alert the host of damage by triggering immune responses. The biological function of HMGB1 is mediated by multiple receptors, including the receptor for advanced glycation end products (RAGE) and Toll-like receptors (TLRs), which are expressed in different hepatic cells. Activation of HMGB1 and downstream signaling pathways are contributing factors in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), and drug-induced liver injury (DILI), each of which involves sterile inflammation, liver fibrosis, ductular reaction, and hepatic tumorigenesis. In this review, we will discuss the critical role of HMGB1 in these pathogenic contexts and propose HMGB1 as a bona fide and targetable DAMP in the setting of common liver diseases.
The vast majority of the reported hydrogen evolution reaction (HER) electrocatalysts perform poorly under alkaline conditions due to the sluggish water dissociation kinetics. Herein, a hybridization ...catalyst construction concept is presented to dramatically enhance the alkaline HER activities of catalysts based on 2D transition metal dichalcogenides (TMDs) (MoS2 and WS2). A series of ultrathin 2D‐hybrids are synthesized via facile controllable growth of 3d metal (Ni, Co, Fe, Mn) hydroxides on the monolayer 2D‐TMD nanosheets. The resultant Ni(OH)2 and Co(OH)2 hybridized ultrathin MoS2 and WS2 nanosheet catalysts exhibit significantly enhanced alkaline HER activity and stability compared to their bare counterparts. The 2D‐MoS2/Co(OH)2 hybrid achieves an extremely low overpotential of ≈128 mV at 10 mA cm−2 in 1 m KOH. The combined theoretical and experimental studies confirm that the formation of the heterostructured boundaries by suitable hybridization of the TMD and 3d metal hydroxides is responsible for the improved alkaline HER activities because of the enhanced water dissociation step and lowers the corresponding kinetic energy barrier by the hybridized 3d metal hydroxides.
Ultrathin 2D hybrids are designed and prepared via surface modification of monolayer MoS2 and WS2 nanosheets by metal (Ni, Co, Fe, Mn) hydroxides, which form a new class of alkaline hydrogen evolution reaction (HER) electrocatalysts. The surface introduction of metal hydroxides can effectively reduce the kinetic barrier of the prior water dissociation step of the alkaline HER reaction.
As Charles Darwin anticipated, living fossils provide excellent opportunities to study evolutionary questions related to extinction, competition, and adaptation. Ginkgo (Ginkgo biloba L.) is one of ...the oldest living plants and a fascinating example of how people have saved a species from extinction and assisted its resurgence. By resequencing 545 genomes of ginkgo trees sampled from 51 populations across the world, we identify three refugia in China and detect multiple cycles of population expansion and reduction along with glacial admixture between relict populations in the southwestern and southern refugia. We demonstrate multiple anthropogenic introductions of ginkgo from eastern China into different continents. Further analyses reveal bioclimatic variables that have affected the geographic distribution of ginkgo and the role of natural selection in ginkgo's adaptation and resilience. These investigations provide insights into the evolutionary history of ginkgo trees and valuable genomic resources for further addressing various questions involving living fossil species.
Optical imaging, especially fluorescence and photoacoustic imaging, is a non‐invasive imaging approach with high spatial and temporal resolution and high sensitivity, compared to positron emission ...tomography (PET) or magnetic resonance imaging (MRI). Due to the merits of imaging using the second near‐infrared (NIR‐II) window, like deeper penetration depth, high signal‐to‐noise ratio, high resolution, and low tissue damage, researchers have devoted great effort to developing contrast agents with NIR‐II absorption or emission. In this Review, we summarize recently developed organic luminescent and photoacoustic materials, ranging from small molecules to conjugated polymers. Then, we systematically introduce engineering strategies and describe the imaging performance classified by the skeleton cores. Finally, we elucidate the challenges and prospects of these NIR‐II organic dyes for potential clinical applications. We expect our summary can inspire researchers to expand the spectrum of NIR‐II contrast agents for diverse bioapplications.
Organic fluorophores in the second near‐infrared (NIR‐II) range have been validated as attractive imaging tools in biomedical research owing to their biocompatibility, flexible chemical structure, and tunable spectra. This Review systematically summarizes recent advances in the chemistry, design principles, and optical properties of NIR‐II organic contrast agents.
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•miR-126 exosomes efficiently transferred miR-126 to the injured spinal cord.•Exosomes containing miR-126 promoted angiogenesis in the spinal cord after SCI by suppressing SPRED1 and ...PIK3R2.•Exosomes containing miR-126 promote neurogenesis and reduce Apoptosis after SCI.
Spinal cord injury (SCI) is a devastating neurological event that results in incomplete or complete loss of voluntary motor and sensory function. Until recently, there has been no effective curative strategy for SCI. Our previous study showed that microRNA (miR)-126 promoted angiogenesis and attenuated inflammation after SCI; however, the effect of miR-126-based treatment is limited because of the low efficiency of miR delivery in vivo. Recently, accumulating evidence has indicated that exosomes can serve as a valuable therapeutic vehicle for miR delivery to the central nervous system (CNS). Thus, the present study aimed to investigate whether exosomes derived from mesenchymal stem cells (MSCs) can be used to deliver miR-126 to treat SCI. In this study, we found that MSCs can load miR-126 into secreted exosomes. In a rat model of SCI, exosomes transferred miR-126 to the injured site of the spinal cord, reduced the lesion volume and improved functional recovery after SCI. Additionally, miR-126-loaded exosomes promoted angiogenesis post-SCI. Moreover, the administration of miR-126 exosomes promoted neurogenesis and reduced cell apoptosis after SCI. In vitro, we observed that exosomes derived from miR-126-modified MSCs promoted the angiogenesis and migration of human umbilical venous endothelial cells (HUVECs) by inhibiting the expression of Sprouty-related EVH1 domain-containing protein 1 (SPRED1) and phosphoinositide-3-kinase regulatory subunit 2 (PIK3R2). In conclusion, our study demonstrated that exosomes derived from MSCs transfected with miR-126 may promote angiogenesis and neurogenesis, inhibit apoptosis and promote functional recovery after SCI. These findings suggest that exosomes derived from miR-126-modified MSCs may serve as a novel potential therapeutic strategy for treating SCI.
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